Chemo Duo Called New Standard for Biliary CA

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Note that the survival advantage of the cisplatin-gemcitabine combination in advanced biliary tract cancer was modest, but was sufficient for the researchers and editorialists to consider it a new standard of care.

The chemotherapy combination improved overall survival by 3.6 months compared with gemcitabine alone in locally advanced or metastatic cases (11.7 versus 8.1 months, hazard ratio 0.64, P<0.001), according to John Bridgewater, MD, PhD, of the University College London Cancer Institute in London, and colleagues.

The only disadvantage in adverse events with the chemotherapy duo was trend for excess neutropenia, they reported in the April 8 issue of the New England Journal of Medicine.

"We believe that it should become the standard for patients with biliary tract cancer and become the basis for further investigations," Bridgewater said in an interview, mirroring the researchers' declaration at last year's American Society of Clinical Oncology meeting, where the trial results were first reported.

This conclusion was echoed by Brian M. Wolpin, MD, MPH, and Robert J. Mayer, MD, both of Harvard and Dana Farber Cancer Institute in Boston.

The survival effect was modest, but a "definite step forward," according to their editorial in the same edition of NEJM.

Cancers of the gallbladder and bile ducts are uncommon, which is in part responsible for the difficulty in defining optimal treatment, they noted.

Prior studies suggested a benefit of palliative chemotherapy in biliary cancer, but they were small, uncontrolled, and only phase II.

Bridgewater's group combined the forces of 37 British centers and included all the patients from their prior phase II trial to overcome the challenge of small numbers for a phase III trial.

Use of gemcitabine as a mainstay of chemotherapy for biliary tract cancer has been based on studies of advanced pancreatic cancer, which shares many molecular and other features with biliary tract cancer, Wolpin and Mayer said.

The researchers decided to add cisplatin because of its additive or synergistic effect with gemcitabine in lung, bladder, and other tumor types.

Participants received gemcitabine alone (1,000 mg/m2) on days one, eight, and 15 every four weeks for six cycles, or followed by cisplatin (25 mg/m2), both given on days one and eight every three weeks for eight cycles.

Patients without disease progression at 12 weeks could continue their regimen for another 12 weeks.

After a median 8.2 months of follow-up, the primary overall survival advantage of combination chemotherapy was accompanied by better tumor control (81.4% versus 71.8% complete), or by partial response or stable disease (P=0.049).

Bridgewater's group noted that biliary obstruction was not considered disease progression without radiologic confirmation of progression.

Adverse events were largely similar between single agent and combination chemotherapy groups (P=0.69 overall).

Grade 3 or 4 neutropenia tended to be more common in the cisplatin–gemcitabine group (15.7% versus 9.5%, P=0.07), while the difference was significant for grade 3 or 4 decreased hemoglobin level (7.6% versus 3.0%, P=0.04) and grade 3 or 4 decreased neutrophil count (25.3% versus 16.6%, P=0.03).

Liver function, though, was significantly worse with standalone gemcitabine (27.1% versus 16.7% grade 3 or 4 abnormal liver-function tests, P=0.01). This was "possibly as a result of inferior disease control and biliary drainage," the investigators wrote.

Biliary tract cancer is clearly chemoresponsive, they concluded in the NEJM paper, "a reality suggested but never proved by extant underpowered clinical data."

However, the results also suggested a limit to the presumed similarities between pancreatic and biliary tract cancers, Bridgewater told MedPage Today.

While median overall survival had never formally been determined for biliary cancer, this study sets the standard benchmark at nearly 12 months for combination treatment, which contrasts with survival of not greater than six months in pancreatic cancer with any kind of treatment, he said.

The study was supported by the University College London Hospitals and University College London Comprehensive Biomedical Research Centre, University College London, Cancer Research United Kingdom, and by an unrestricted educational grant from Lilly Oncology.

Two of Bridgewater's co-authors reported conflicts of interest with Eli Lilly.

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